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WO2007016209A2 - Sel de sodium d'acide 1,2-benzisoxazole-3-methane-sulfonique pur et procede de purification - Google Patents

Sel de sodium d'acide 1,2-benzisoxazole-3-methane-sulfonique pur et procede de purification Download PDF

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Publication number
WO2007016209A2
WO2007016209A2 PCT/US2006/029121 US2006029121W WO2007016209A2 WO 2007016209 A2 WO2007016209 A2 WO 2007016209A2 US 2006029121 W US2006029121 W US 2006029121W WO 2007016209 A2 WO2007016209 A2 WO 2007016209A2
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WO
WIPO (PCT)
Prior art keywords
benzisoxazole
methane
sulfonic acid
sodium salt
acid sodium
Prior art date
Application number
PCT/US2006/029121
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English (en)
Other versions
WO2007016209A3 (fr
Inventor
Marioara Mendelovici
Natalia Shenkar
Original Assignee
Teva Pharmaceutical Industries Ltd.
Teva Pharmaceuticals Usa, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Teva Pharmaceutical Industries Ltd., Teva Pharmaceuticals Usa, Inc. filed Critical Teva Pharmaceutical Industries Ltd.
Publication of WO2007016209A2 publication Critical patent/WO2007016209A2/fr
Publication of WO2007016209A3 publication Critical patent/WO2007016209A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

  • the present invention concerns chemically pure sodium salt of l,2-benzisoxazole-3- methane sulfonic acid (BOS-Na), a process for purifiying the sodium salt and a process for preparing zonisamide using the BOS-Na.
  • BOS-Na l,2-benzisoxazole-3- methane sulfonic acid
  • BOS-H l,2-Benzisoxazole-3-methane ⁇ sulfonic acid
  • BOS-H can be prepared by a sulfonation reaction as described in WO 2004/020419. The reaction product may be isolated as the sodium salt, calcium salt or barium salt of BOS-H.
  • WO 2004/020419 also discloses polymorphic forms of BOS-H and salts of BOS-H (BOS-salts).
  • BOS-H free acid is known to be a highly hygroscopic compound.
  • the alkaline and alkaline-earth salts (sodium salt, barium salt, calcium salt) of BOS-H are also hygroscopic. (Siggia, Quantitative Organic Analysis of Functional Groups, 4 th edition, p. 792; C. Sutter, The Organic Chemistry of Sulfur, the 1946 edition, John Wiley & Sons, N. Y.).
  • Prior art processes for the preparation of the sodium salt, i.e. BOS-Na, of BOS-H are disclosed in JP 53-77053 and usually include adding aqueous NaOH to a reaction mixture containing BOS-H.
  • BOS-Na obtained for example, according to the process disclosed in JP 53-77053 is a white solid having a relative high content of inorganic salts, and generally has an assay of only 85-90% or at most, of about 92 to 95%.
  • WO 03/072552 discloses the preparation of zonisamide starting with BOS-H or a
  • BOS-salt and chlorinating the BOS-H or BOS-salt to form l,2-benzisoxazole-3-methane- sulfonyl chloride (BOS-Cl) followed by amidation, wherein the BOS-Cl can be represented by formula (II).
  • the present invention provides chemically pure BOS-Na.
  • the present invention provides BOS-Na of high assay.
  • the present invention provides chemically pure BOS-Na of high assay. In one of the embodiments, the present invention provides a process for purifying
  • BOS-Na comprising the steps of: combining BOS-Na, at least one Cj-C 4 alcohol and water to form a mixture; heating the mixture; and recovering the BOS-Na from the heated mixture.
  • the present invention provides a process for preparing BOS-Cl from BOS-Na, comprising the steps of: combining BOS-Na with an inert organic solvent and a chlorinating agent to form a reaction mixture; heating the reaction mixture; and removing the inert organic solvent and any excess of the chlorinating agent from the heated reaction mixture to obtain BOS-Cl as a residue.
  • the stalling BOS-Na preferably is purified by the BOS-Na purification process of the present invention.
  • the present invention provides a process for preparing zonisamide comprising obtaining BOS-Cl according to the BOS-Cl producing process of the present invention and converting the BOS-Cl to zonisamide.
  • the present invention provides a pharmaceutical composition of zonisamide prepared according to the zonisamide producing process of the present invention, and at least one pharmaceutically acceptable excipient.
  • the present invention provides a process for preparing a pharmaceutical formulation comprising combining zonisamide prepared according to the zonisamide producing process of the present invention with at least one pharmaceutically acceptable excipient.
  • the present invention provides the use of zonisamide prepared according to the present invention, for the manufacture of a pharmaceutical composition.
  • the term "chemically pure" referring to BOS-Na means BOS-Na having a chemical purity of about 98 area% to about 100 area% as determined by HPLC.
  • test in reference to BOS-Na refers to the content, expressed as percent of the total sample weight, of BOS-Na in a BOS-Na sample.
  • the BOS-Na sample may contain residual water, other residual solvents and other salts in addition to BOS-Na.
  • the term "high assay" in reference to BOS-Na means BOS-Na having an assay of about 95% to about 100%. In preferred embodiments of the BOS-Na of the present invention, the BOS-Na has an assay of preferably about 98% to about 100%.
  • crude refers to a compound that has not undergone further purification by any known methods, such as, crystallization or suspension in appropriate solvents.
  • aromatic solvent refers to a C 6-1O aromatic hydrocarbon such as but not limited to benzene, xylene, or toluene.
  • cooling gradually to a target temperature means cooling a sample starting with the original sample temperature to reach the target temperature in a cooling duration ranging from about 20 minutes to about 210 minutes, preferably ranging from about 30 minutes to about 180 minutes, e.g., about 30 minutes, and more preferably ranging from about 60 minutes to about 180 minutes or ranging from about 120 minutes to about 180 minutes, e.g., about 60 minutes, about 120 minutes, or most preferably about 180 minutes.
  • anhydrous refers to a water content of less than about 200 ppm.
  • an “anhydrous” substance or “anhydrous conditions” used in the present invention can have a water content less than about 20 ppm.
  • Inorganic salts may be removed from an organic compound by slurrying in water, but this procedure is not operable in the case of the salts of BOS-H due to their high water solubility.
  • the present invention provides chemically pure BOS-Na.
  • the BOS-Na has a chemical purity of about 99 to about 100 area %, more preferably, of about 99.5 to about 100 area %, and most preferably of about 100 area %, as determined by HPLC.
  • the present invention also provides BOS-Na of high assay.
  • the BOS-Na has an assay of about 98% to about 100%, more preferably, about 99% to about 100%, and most preferably about 100%, by HPLC.
  • the present invention further provides chemically pure BOS-Na of high assay. Also provided by the present invention is a process for purifying BOS-Na comprising the steps of: combining BOS-Na, at least one C 1 -C 4 alcohol and water to form a mixture; heating the mixture; and recovering the BOS-Na from the heated mixture.
  • the BOS-Na to be purified in the above process may be obtained by any of the prior art processes, for example, the processes disclosed in WO 03/020708.
  • a slurry is obtained after combining BOS-Na, the at least one Ci-C 4 alcohol and water.
  • the slurry contains a total Ci-C 4 alcohol:water volume ratio of about 10:90 to about 99:1, more preferably, about 50:50 to about 97:3, more preferably, about 70:30 to about 95:5, and , most preferably about 90:10, wherein the combined volumes of any Ci-C 4 alcohols present in the slurry is used in calculating the total Ci-C 4 alcohol:water volume ratio.
  • the Ci-C 4 alcohol is ethanol.
  • the mixture is heated to reflux temperature.
  • a solution is obtained.
  • any insoluble material may be removed from the solution by filtering.
  • the filtrate obtained after removing the insoluble material may be reheated to reflux.
  • the hot filtrate may be cooled prior to the recovery step, to obtain a precipitate of BOS-Na.
  • the cooling of the hot filtrate is conducted, preferably gradually, to a temperature of about O 0 C to about -1O 0 C, more preferably to a temperature of about -5°C, to precipitate BOS- Na.
  • the precipitated BOS-Na can then be recovered as a chemically pure BOS-Na, BOS-Na of the high assay, or chemically pure BOS-Na of the high assay.
  • Gradual cooling of the BOS- Na solution increases the purity of the precipitated BOS-Na, while cooling to a low temperature increases the yield.
  • the BOS-Na yield is about 90% or higher, preferably the yield is about 92%.
  • Direct cooling of the BOS-Na to about O 0 C achieves a crystallization yield ranging from about 80% to less than about 90%, preferably about 84%.
  • the BOS-Na obtained after the recovering procedure is chemically pure
  • BOS-Na BOS-Na of a high assay
  • BOS-Na of a high assay or chemically pure BOS-Na of a high assay.
  • the recovery procedure is done by any methods known in the art, such as filtering the precipitate, washing and optionally, drying in a vacuum oven.
  • the obtained BOS-Na is BOS-Na monohydrate, which is optionally dried to give anhydrous BOS-Na.
  • Also encompassed by the present invention is a process for preparing BOS-Cl from BOS-Na, comprising the steps of: combining BOS-Na with at least one inert organic solvent (wherein the at least one inert organic solvent can be selected from inert polar organic solvents, inert non-polar organic solvents and mixtures thereof) and a chlorinating agent to form a reaction mixture; heating the reaction mixture; and removing the at least one inert organic solvent and any excess of the chlorinating agent from the heated reaction mixture to obtain BOS-Cl as a residue.
  • at least one inert organic solvent can be selected from inert polar organic solvents, inert non-polar organic solvents and mixtures thereof
  • the starting BOS-Na is anhydrous.
  • BOS-Na monohydrate of the present invention is dried to obtain the anhydrous BOS-Na.
  • the starting BOS-Na for the BOS-Cl producing process is chemically pure BOS-Na 5 BOS-Na of a high assay, or chemically pure BOS-Na of a high assay.
  • the at least one inert organic solvent is selected from the group consisting of: ethyl acetate, chlorobenzene, ethers, THF, MTBE, chloroform, methylene chloride, dichloroethane, dichloromethane, toluene and mixtures thereof.
  • the at least one inert organic solvent is at least one inert aromatic solvent.
  • the at least one inert aromatic solvent is toluene.
  • the chlorinating agent is selected from the group consisting of: PCl 3 , PCl 5 , POCl 3 and thionyl chloride. More preferably, the chlorinating agent is thionyl chloride.
  • the process further comprises adding a catalyst to the slurry.
  • the catalyst is preferably a formamide, more preferably, a N,N-disubstituted formamide and most preferably, dimethyl formamide (DMF).
  • a slurry is obtained prior to the heating.
  • the slurry is heated while being stirred vigorously.
  • the slurry is heated is to a temperature of, preferably about 4O 0 C to about 8O 0 C, and more preferably about 5O 0 C.
  • the excess of the chlorinating agent and the at least one inert organic solvent are removed by evaporation or distillation at reduced pressure.
  • the BOS-Cl residue obtained after the removal of the at least one inert organic solvent and chlorinating agent is recovered by any method known in the art, such as suspending in an inert organic solvent, preferably toluene, and filtering to remove any inorganic impurities, such as NaCl.
  • the present invention further encompasses a process for preparing zonisamide comprising obtaining BOS-Cl according to the BOS-Cl producing process of the present invention and converting the BOS-Cl to zonisamide.
  • the conversion may be done according to the disclosures of WO 03/072552.
  • the BOS-Cl can be converted to zonisamide with a process comprising reacting the BOS-Cl with ammonia.
  • the conversion of BOS-Cl to zonisamide may also be performed according to the disclosures of JP 53-77057 or US 4,172,896..
  • the BOS-Cl residue is combined with at least one inert organic solvent (wherein the at least one inert organic solvent can be selected from inert polar organic solvents, inert non-polar organic solvents and mixtures thereof) and ammonia to form a crude zonisamide precipitate.
  • the ammonia is added to obtain a basic suspension with a pH, preferably, of about 9.
  • the ammonia can be gaseous ammonia, and preferably anhydrous, gaseous ammonia. More preferably, the reaction of the BOS-Cl and ammonia in the at least one inert organic solvent is conducted under anhydrous conditions.
  • the BOS-Cl is mixed with the at least one inert organic solvent at a temperature of about 2 0 C, or the BOS-Cl is mixed with the at least one inert organic solvent to form a mixture and the mixture is cooled to a temperature of about 2°C.
  • the BOS-Cl is combined with the at least one inert organic solvent and the ammonia at a temperature of about 2 0 C.
  • the at least one inert organic solvent is an at least one inert aromatic solvent. More preferably, the at least one inert aromatic solvent is toluene.
  • the crude zonisamide may be recovered.
  • the recovery comprises adding a mineral acid, preferably HCl, filtering and washing with water.
  • the crude zonisamide may be further purified, e.g., by chromatography or by crystallization from a solvent.
  • the purification comprises heating a solution of the crude zonisamide in at least one Ci-C 4 alcohol, preferably ethanol, to reflux.
  • the crystals of pure zonisamide may be isolated from the hot solution by any method known in the art, such as, cooling to induce precipitation and filtering.
  • the present invention also provides a pharmaceutical composition comprising zonisamide prepared according to the process of the present invention, and at least one pharmaceutically acceptable excipient.
  • the present invention further encompasses a process for preparing a pharmaceutical composition
  • a process for preparing a pharmaceutical composition comprising combining zonisamide prepared according to the process of the present invention, with at least one pharmaceutically acceptable excipient.
  • the present invention further encompasses the use of zonisamide prepared according to the process of the present invention, for the manufacture of a pharmaceutical composition.
  • compositions of the present invention can be administered in various preparations depending on the age, sex, and symptoms of the patient.
  • the pharmaceutical compositions can be administered, for example, as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injection preparations (solutions and suspensions), and the like.
  • the pharmaceutical composition of the present invention can optionally include more than one form of zonisamide prepared according to the process of the present invention and/or at least one other pharmaceutically active ingredient.
  • the pharmaceutical composition of the present invention can contain inactive ingredients such as diluents, carriers, fillers, bulking agents, binders, disintegrants, disintegration inhibitors, absorption accelerators, wetting agents, lubricants, glidants, surface active agents, flavoring agents, and the like.
  • Diluents increase the bulk of a solid pharmaceutical composition and can make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle.
  • Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel®), microfine cellulose, lactose, starch, pregelitinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, or talc.
  • microcrystalline cellulose e.g., Avicel®
  • microfine cellulose lactose
  • starch pregelitinized starch
  • calcium carbonate calcium sulfate
  • sugar dextrates
  • Carriers for use in the pharmaceutical compositions may include, but are not limited to, lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, or silicic acid.
  • Binders help bind the active ingredient and other excipients together after compression.
  • Binders for solid pharmaceutical compositions include for example acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, or starch.
  • carbomer e.g. carbopol
  • carboxymethylcellulose sodium dextrin
  • ethyl cellulose gelatin
  • guar gum hydrogenated vegetable oil
  • hydroxyethyl cellulose hydroxypropyl cellulose
  • Disintegrants can increase dissolution.
  • Disintegrants include, for example, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab®) and starch.
  • alginic acid carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powder
  • Disintegration inhibitors may include, but are not limited to, white sugar, stearin, coconut butter, hydrogenated oils, and the like.
  • Absorption accelerators may include, but are not limited to, quaternary ammonium base, sodium laurylsulfate, and the like .
  • Wetting agents may include, but are not limited to, glycerin, starch, and the like.
  • Adsorbing agents used include, but are not limited to, starch, lactose, kaolin, bentonite, colloidal silicic acid, and the like .
  • Lubricants include for example magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
  • Glidants can be added to improve the flowability of non-compacted solid composition and improve the accuracy of dosing.
  • Excipients that can function as glidants include for example colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
  • Flavoring agents and flavor enhancers make the dosage form more palatable to the patient.
  • Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present invention include for example maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
  • Tablets can be further coated with commonly known coating materials such as sugar coated tablets, gelatin film coated tablets, tablets coated with enteric coatings, tablets coated with films, double layered tablets, and multi-layered tablets.
  • Capsules can be coated with shell made, for example, from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
  • Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
  • liquid pharmaceutical compositions of the present invention zonisamide prepared according to the process of the present invention and any other solid ingredients are dissolved or suspended in a liquid carrier, such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
  • a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
  • Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier.
  • Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol.
  • Liquid pharmaceutical compositions of the present invention can also contain viscosity enhancing agents to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract.
  • agents include for example acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.
  • Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar can be added to improve the taste.
  • Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid can be added at safe levels to improve storage stability.
  • a liquid composition according to the present invention can also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate.
  • a composition for tableting or capsule filing can be prepared by wet granulation.
  • wet ' granulation some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, which causes the powders to clump up into granules.
  • the granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size.
  • the granulate can then be tabletted or other excipients can be added prior to tabletting, such as a glidant and/or a lubricant.
  • a tabletting composition can be prepared conventionally by dry blending.
  • the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules.
  • the compacted granules can be compressed subsequently into a tablet.
  • a blended composition can be compressed directly into a compacted dosage form using direct compression techniques.
  • Direct compression produces a more uniform tablet without granules.
  • Excipients that are particularly well-suited to direct compression tabletting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tabletting is known to those in the art with experience and skill in particular formulation challenges of direct compression tabletting.
  • a capsule filling of the present invention can comprise any of the aforementioned blends and granulates that were described with reference to tabletting, only they are not subjected to a final tabletting step.
  • any commonly known excipient used in the art can be used.
  • carriers include, but are not limited to, lactose, starch, coconut butter, hardened vegetable oils, kaolin, talc, and the like.
  • Binders used include, but are not limited to, gum arabic powder, tragacanth gum powder, gelatin, ethanol, and the like.
  • Disintegrating agents used include, but are not limited to, agar, laminalia, and the like .
  • excipients include, but are riot limited to, polyethylene glycols, coconut butter, higher alcohols, esters of higher alcohols, gelatin, semisynthesized glycerides, and the like.
  • solutions and suspensions are sterilized and are preferably made isotonic to blood. Injection preparations may use carriers commonly known in the art.
  • carriers for injectable preparations include, but are not limited to, water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyoxyethylene sorbitan.
  • water ethyl alcohol
  • propylene glycol ethoxylated isostearyl alcohol
  • polyoxylated isostearyl alcohol ethoxylated isostearyl alcohol
  • fatty acid esters of polyoxyethylene sorbitan ethyl alcohol
  • carriers for injectable preparations include, but are not limited to, water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyoxyethylene sorbitan.
  • One of ordinary skill in the art can easily determine with little or no experimentation the amount of sodium chloride, glucose, or glycerin necessary to make the injectable preparation isot
  • excipients mentioned above are merely examples of excipients that can be included in the pharmaceutical compositions of the present invention, and are not meant to be all inclusive. Excipients not specifically mentioned herein can be included in the pharmaceutical compositions of the present invention.
  • the amount of zonisamide prepared according to the process of the present invention contained in a pharmaceutical composition according to the present invention is not specifically restricted; however, the dose should be sufficient to treat, ameliorate, or reduce the condition.
  • Example 1 Purification of BOS-Na
  • a batch of BOS-Na (30 g) (batch number 2002003, assay by HPLC 92.3% pure) was suspended in 600 ml ethanol containing 10% v/v water and heated to reflux. Almost all the solid was dissolved; the insoluble material was filtered from the hot slurry. The filtrate was then reheated to reflux and gradually cooled to a temperature of -5 0 C. The solid was filtered, washed with ethanol and dried at 8O 0 C under vacuum until the water content (via the Karl Fischer technique) is less than 1.5%. The crystallized material weighed 25.44 g having an improved assay and purity (assay and purity by HPLC 100%, K.F.
  • a 0.25 1 three necked flask equipped with condenser, thermometer and mechanical stirrer was charged at a temperature in the range 25-27 0 C, with purified BOS-Na (20 g), technical toluene (150 m and DMF (0.66 ml), to obtain a reaction slurry.
  • the BOS-Na was purified by the procedure similar to one described in Example 1.
  • thionyl chloride (24.6 ml) was added drop-wise o 30 minutes.
  • the reaction mixture was then heated to 5O 0 C under nitrogen atmosphere, and stirred with stirring rate of about 200-215 rpm.

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Abstract

L'invention porte sur un sel de sodium d'acide 1,2-benzisoxazole-3-méthane-sulfonique chimiquement pur, un sel de sodium d'acide 1,2-benzisoxazole-3-méthane-sulfonique à titre élevé, ou un sel de sodium d'acide 1,2-benzisoxazole-3-méthane-sulfonique chimiquement pur à titre élevé, et des procédés permettant de préparer ceux-ci par un processus de purification. L'invention concerne également une forme monohydrate du sel de sodium d'acide 1,2-benzisoxazole-3-méthane-sulfonique chimiquement pur, du sel de sodium d'acide 1,2-benzisoxazole-3-méthane-sulfonique à titre élevé, ou du sel de sodium d'acide 1,2-benzisoxazole-3-méthane-sulfonique chimiquement pur à titre élevé. L'invention concerne en outre une forme anhydre du sel de sodium d'acide 1,2-benzisoxazole-3-méthane-sulfonique chimiquement pur, du sel de sodium d'acide 1,2-benzisoxazole-3-méthane-sulfonique à titre élevé, ou de sel de sodium d'acide 1,2-benzisoxazole-3-méthane-sulfonique chimiquement pur à titre élevé. Dans une forme de réalisation, l'invention concerne un procédé permettant de préparer du zonisamide avec ce sel de sodium d'acide 1,2-benzisoxazole-3-méthane-sulfonique chimiquement pur, du sel de sodium d'acide 1,2-benzisoxazole-3-méthane-sulfonique à titre élevé, ou de sel de sodium d'acide 1,2-benzisoxazole-3-méthane-sulfonique chimiquement pur à titre élevé.
PCT/US2006/029121 2005-07-28 2006-07-28 Sel de sodium d'acide 1,2-benzisoxazole-3-methane-sulfonique pur et procede de purification WO2007016209A2 (fr)

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US60/702,994 2005-07-28

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WO2007016209A3 WO2007016209A3 (fr) 2007-04-12

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JP2005526049A (ja) * 2002-02-22 2005-09-02 テバ ファーマシューティカル インダストリーズ リミティド ベンゾイソキサゾールメタンスルホニルクロリドの調製及びゾニスアミドを形成するためのそのアミド化の方法
AU2003304484A1 (en) * 2003-09-29 2005-04-14 Suven Life Sciences Limited Improved process for the preparation of intermediates useful for the preparation of zonisamide

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